How the humble hen's egg can be turned into a powerful weapon to treat disease...
The simple chickenís egg has long been known as a symbol of new life. But less well known is that eggs can be turned into incubators to produce a raft of other molecules, including agents to combat infection.
The human immune system responds to foreign substances by producing antibodies, which are specialised proteins that bind to invading organisms and toxins, block their activity and target them for destruction by other members of the immune infantry. Antibodies also circulate for extended periods in the blood, providing long-term protection against any of the same bugs that might try to make a comeback, and mothers protect their offspring by siphoning off some of their own antibodies and adding of them to the foetal circulation during the latter part of pregnancy. The same is also true of chickens, but with the difference that they add their antibodies to the yolks of the eggs they lay.
Therein lies a therapeutic opportunity. Because exposure to specific viruses or bacteria triggers chickens to produce antibodies against these organisms. And if a chicken is injected with samples of the same pathogens, this also achieves the same effect. In fact, within just a few weeks, every egg the chicken lays will contain high levels of antibodies specifically targeting those viruses or bacteria. Moreover, these antibodies can be purified from the yolks to produce what is almost antibodies on-tap.
But how can these egg-yolk-antibodies be used to treat infections? Giving pre-formed antibodies to people who have been exposed to a particular infectious agent has long been recognised as a way of limiting disease. Historically, these antibodies have been obtained from horses or humans, but there have been several problems associated with using this technique. Horses can produce large amounts of antibody for human use, but severe hypersensitivity (allergic) reactions can develop in some people. This is because the human body recognises the horse proteins as foreign and mounts its own, occasionally overzealous response. Human antibodies bind to the horse antibodies, forming molecular complexes, which clog up small blood vessels, settle in joints and sometimes attack the kidneys, resulting in a condition called serum sickness. To avoid this issue, the only antibodies currently used therapeutically in this way in the UK are obtained from healthy human donors. These are individuals who have previously been vaccinated against the agent for which antibodies are needed. These antibodies are collected by purifying them from the blood of the donors. This method is consequently inefficient and expensive.
The strategy of giving pre-made antibodies to fight infection is known as passive immunization. Following exposure to any new pathogen, a normal immune system takes at least five days to produce its own antibodies. For some infections this is too long. Certain bacteria and viruses are exceptionally good at surviving inside cells where antibodies offer little protection. Instead, immediate treatment with antibodies from other sources helps to eliminate these invading pathogens before they have a chance to invade and replicate.
There are three viruses and a bacterium for which passive immunization is currently available in the UK. These are rabies virus, hepatitis B virus, varicella-zoster virus and tetanus (C. tetani) bacteria.
Rabies virus is almost universally fatal if allowed to take hold. But passive immunisation administed rapidly following exposure can help to prevent this. Hepatitis B virus typically causes short-term liver disease and is eliminated from the body, but in 5-10% of cases (and in 80% of individuals infected as infants) it causes a life-long persistent infection. This can lead to development of liver cirrhosis and cancer. Stopping the virus in its tracks at the time of exposure is essential. Varicella-zoster virus is more commonly known as the cause of chicken pox, and preformed antibodies are useful for protecting pregnant women who have not previously been infected, and individuals with a weakened immune system for whom the illness can be fatal. The final example is C. tetani, the cause of tetanus. This bacterium can gain entry to the body via dirty wounds and will induce severe muscle spasms if it not blocked by the appropriate antibodies.
So we know antibodies are extremely useful molecules for medicinal use, but because horse antibodies are risky, and human antibodies have limited availability, chicken egg antibodies might be a valuable addition to our medical arsenal. Eggs are plentiful and easily harvested. Just four eggs can produce as much antibody as an entire guinea pig. More importantly, the human immune system tolerates chicken antibodies much better than antibodies from horses.
The effectiveness of chicken egg antibodies has been tested in laboratories against a wide variety of viruses and bacteria including rotaviruses, which cause of diarrhea in infants, and the dreaded noroviruses that cause gastroenteritis in 3 million people in the UK every year. Studies have shown that chicken egg antibodies are also active against Helicobacter pylori, the primary cause of gastric ulcers and, experimentally, and, in tests on mice, can also limit disease caused by Vibrio parahaemolyticus, a bacterium responsible for many outbreaks of gastroenteritis following ingestion of undercooked seafood.
But how close are we to using chickens to produce antibodies for infectious disease treatment for the general public? It has been almost twenty years since the first studies using egg antibody to treat viral disease in animals were published. Back in 1994, a team of Japanese scientists first showed that calves could be protected against bovine rotavirus using chicken egg antibodies.
In the past decade there have been a handful of clinical trials investigating the use of egg antibodies for infectious disease treatment in humans. In Bangladesh in 2001, human rotavirus-inoculated chickens were used to produce egg antibodies that improved clinical outcomes in rotavirus-infected children. A similar study conducted in Myanmar and published in 2012, administered anti-rotavirus egg antibodies in a banana flavoured drink four times a day for 8 days to 26 rotavirus-infected children. A further 26 children were given a placebo drink at the same intervals. The children were otherwise treated identically, including receiving supportive therapy for diarrhoea. The results were very encouraging. The antibody-treated group needed less rehydration therapy and their diarrhoeal symptoms resolved more rapidly. Critically, no hypersensitivity side effects were reported.
Studies are also currently underway to explore the effectiveness of egg-antibodies in the treatment of the infections caused by the bacterium Pseudomonas aeruginosa, has now reached phase III clinical trials that are due to be completed in September 2014. This means it is one step away from being granted approval by medical governing bodies, thus becoming the first egg antibody to be used in clinical practice. Pseudomonads are opportunistic bacteria that frequently cause lung infections (pneumonia) in patients with cystic fibrosis (CF) owing to the build up of thick mucus in their lungs. In a 2008 study on CF sufferers, the incidence of pseudomonas infection amongst patients to whom egg-antibodies had been administered was three fold less at 2.3 cases per 100 months compared with a control group of untreated patients.
Overall, it looks likely that the first mainstream therapeutic egg antibodies will make it into the fridges of hospital pharmacies within a few years. Most likely these antibodies will be used against just a handful of infectious infectious disease agents to start with, but many more experimental trials, with many more people in many more countries, will see this number increase significantly over the decades to come. From now on I will admire chickens that little bit more...